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Elucidating the Role of Translocator Protein in Prostate Cancer: Implications as a Therapeutic Target for Advanced Disease

Fafalios, Arlee Elizabeth
(2009)
Elucidating the Role of Translocator Protein in Prostate Cancer: Implications as a Therapeutic Target for Advanced Disease.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)

Abstract

BackgroundProstate cancer is the second leading cause of cancer related death in men. Current therapies for metastatic prostate cancer can only prolong progression, as most men eventually succumb to metastasis and then death. Therefore, there is continued urgency to identify novel therapeutic targets for advanced disease. Previous reports have identified an increase in Translocator Protein (TSPO) expression in numerous cancer models, including prostate. Functionally, TSPO has been implicated in the regulation of apoptosis and cell proliferation. Here, the role of TSPO in advanced prostate cancer is evaluated in an effort to establish the potential value of TSPO as a therapeutic target in advanced disease.Methodology and Principle FindingsImmunohistochemical analysis using tissue microarrays was used to determine the expression profile of TSPO in human prostate cancer tissues. We observed that TSPO expression increases with disease progression, as prostate cancer metastases had the highest expression. To demonstrate the effect of TSPO ligands PK11195 and lorazepam in prostate cancer, we utilized cell proliferation assays, cell death ELISAs, and a prostate cancer mouse xenograft study. Our findings provide the first evidence of the anti-tumor effects of lorazepam acting on TSPO. To determine the effect of modulating TSPO expression, we performed overexpression and knockdown studies. These studies provided further evidence that lorazepam is acting through TSPO, as overexpression of TSPO conferred increased susceptibility to lorazepam while TSPO knockdown decreased susceptibility. Lastly, we investigated the role of TSPO multimers in prostate cancer. We found that TSPO multimers can be induced by reactive oxygen species and may be formed through a di-tyrosine covalent bond. Conclusions and SignificanceTSPO expression increases with prostate cancer progression. The benzodiazepine lorazepam exerts its anti-cancer effects through its binding to TSPO. Collectively, these data suggest that TSPO is an excellent therapeutic target for advanced disease and that our preclinical results demonstrating that the already existing FDA-approved drug lorazepam has anti-tumor effects could be easily translated to the prostate cancer patient population. These studies could lead to a significant change in the management of prostate cancer by providing a treatment option with minimal toxicity for use in advanced disease and could ultimately prevent prostate cancer deaths.